Drug Delivery Device

ABSTRACT

The invention relates to a disposable drug delivery device for selecting and dispensing a number of user variable doses of a medicament. The device comprises a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/137,262, filed Apr. 25, 2016, which is a continuation ofU.S. patent application Ser. No. 14/423,733, filed Feb. 25, 2015, nowU.S. Pat. No. 9,345,838, which is a U.S. National Phase Applicationpursuant to 35 U.S.C. § 371 of International Application No.PCT/EP2013/067863 filed Aug. 29, 2013, which claims priority to EuropeanPatent Application No. 12182568.1 filed Aug. 31, 2012, and U.S.Provisional Patent Application No. 61/697,078, filed Sep. 5, 2012. Theentire disclosure contents of these applications are herewithincorporated by reference into the present application.

TECHNICAL FIELD

The present invention is generally directed to drug delivery devices.More particularly, the present invention is directed to disposable drugdelivery devices.

BACKGROUND

Pen type drug delivery devices have application where regular injectionby persons without formal medical training occurs. This may beincreasingly common among patients having diabetes where self-treatmentenables such patients to conduct effective management of their disease.In practice, such a drug delivery device allows a user to individuallyselect and dispense a number of user variable doses of a medicament. Thepresent invention is not directed to so called fixed dose devices whichonly allow dispensing of a predefined dose without the possibility toincrease or decrease the set dose.

There are basically two types of drug delivery devices: resettabledevices (i.e., reusable) and non-resettable (i.e., disposable). Forexample, disposable pen delivery devices are supplied as self-containeddevices. Such self-contained devices do not have removable pre-filledcartridges. Rather, the pre-filled cartridges may not be removed andreplaced from these devices without destroying the device itself.Consequently, such disposable devices need not have a resettable dosesetting mechanism.

These types of pen delivery devices (so named because they oftenresemble an enlarged fountain pen) are generally comprised of threeprimary elements: a cartridge section that includes a cartridge oftencontained within a housing or holder; a needle assembly connected to oneend of the cartridge section; and a dosing section connected to theother end of the cartridge section. A cartridge (often referred to as anampoule) typically includes a reservoir that is filled with a medication(e.g., insulin), a movable rubber type bung or stopper located at oneend of the cartridge reservoir, and a top having a pierceable rubberseal located at the other, often necked-down, end. A crimped annularmetal band is typically used to hold the rubber seal in place. While thecartridge housing may be typically made of plastic, cartridge reservoirshave historically been made of glass.

The needle assembly is typically a replaceable double-ended needleassembly. Before an injection, a replaceable double-ended needleassembly is attached to one end of the cartridge assembly, a dose isset, and then the set dose is administered. Such removable needleassemblies may be threaded onto, or pushed (i.e., snapped) onto thepierceable seal end of the cartridge assembly.

The dosing section or dose setting mechanism is typically the portion ofthe pen device that is used to set a dose. During an injection, aspindle or piston rod contained within the dose setting mechanismpresses against the bung or stopper of the cartridge. This force causesthe medication contained within the cartridge to be injected through anattached needle assembly. After an injection, as generally recommendedby most drug delivery device and/or needle assembly manufacturers andsuppliers, the needle assembly is removed and discarded.

Disposable and reusable drug delivery devices have certain perceiveddisadvantages. One perceived disadvantage is that such devices have ahigh number of parts and therefore such devices are typicallycomplicated from a manufacturing and from an assembly standpoint. Inaddition, because such devices use a large number of components parts,such devices tend to be large and bulky, and therefore not easy to carryaround or easy to conceal.

SUMMARY

A disposable drug delivery device according to the present inventiontypically comprises a housing, a cartridge holder for retaining acartridge containing a medicament, a piston rod displaceable relative tothe cartridge holder, a driver coupled to the piston rod, a displaymember for indicating a set dose and being coupled to the housing and tothe driver, and a button coupled to the display member and to thedriver. The device is delivered to the user in a fully assembledcondition ready for use. Such a disposable drug delivery device is knowne.g. from WO 2004/078241 A1.

It is an object of the present invention to provide an improved drugdelivery device which has a reduced number of component parts andreduced manufacturing costs while also making the device less complex toassemble and manufacture. It is a further object to simplify the stepsrequired for a user to set and dispense a dose while also making thedevice less complex and more compact in size.

According to a first embodiment of the present invention, this object issolved by a disposable drug delivery device for selecting and dispensinga number of user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, and a button coupledto the display member and to the driver, wherein the housing comprisesan outer body and an inner body with the outer body being a one-piececomponent with the cartridge holder. Combining the cartridge holder andthe outer body part of the housing into one single component reduces thenumber of component parts and thus assembling complexity. Further, therisk of a misuse, where a user attempts to exchange an empty cartridgein a disposable drug delivery device, is reduced.

According to a second embodiment of the present invention, this objectis solved by a disposable drug delivery device for selecting anddispensing a number of user variable doses of a medicament, comprising ahousing, a cartridge holder for retaining a cartridge containing themedicament, a piston rod displaceable relative to the cartridge holder,a driver coupled to the piston rod, a display member for indicating aset dose and being coupled to the housing and to the driver, and abutton coupled to the display member and to the driver, wherein thedriver is in threaded engagement with the piston rod, permanentlyrotationally locked to the button and axially displaceable relative tothe button in a proximal direction against the force of a resilientmember which is a one piece component with either the driver or thebutton (or the button is displaceable relative to the driver in a distaldirection). In other words, a spring or the like resilient member forbiasing the button in a first direction which is usually provided as aseparate component in known devices is integrated in the button ordriver to thus reduce the number of component parts and assemblingcomplexity.

Preferably, the driver comprises at least one elastically deformablefinger having a free end engaging the button to bias the button in theproximal direction.

According to a third embodiment of the present invention, this object issolved by a disposable drug delivery device for selecting and dispensinga number of user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, and a button coupledto the display member and to the driver, wherein the housing comprisesan inner surface with splines and the driver comprises at least oneprotrusion which in a first axial position of the button relative to thedriver is allowed to elastically move in a radial direction and which ina second axial position of the button relative to the driver is forcedby the button in a radially outer position thus rotationally locking thedriver to the housing. In known devices a clutch member rotationallycoupling the driver and the housing or a clicker member for producing atactile and/or audible feedback during use of the device is usuallyprovided with at least one separate component. In the present embodimentof the invention, these functions of the device are realized withoutadding component parts.

Preferably, the driver comprises at least one protrusion interactingwith splines of the housing wherein the protrusion is elasticallymovable in a radial direction, and wherein the button comprises a recessor opening suitable for at least partly receiving the protrusion of thedriver. If the button is moved relative to the driver, the protrusioncannot engage the recess or opening such that the radially inwardmovement of the protrusion is prevented, thus locking the protrusion inits radial position.

According to a fourth embodiment of the present invention, this objectis solved by a disposable drug delivery device for selecting anddispensing a number of user variable doses of a medicament, comprising ahousing, a cartridge holder for retaining a cartridge containing themedicament, a piston rod displaceable relative to the cartridge holder,a driver coupled to the piston rod, a display member for indicating aset dose and being coupled to the housing and to the driver, and abutton coupled to the display member and to the driver, wherein a firstrotationally acting clutch is formed by the button and the displaymember which is in its coupled state during dose setting and in itsdecoupled state during dose dispensing, and a second rotationally actingclutch is formed by the driver and the housing which is in its decoupledstate during dose setting and in its coupled state during dosedispensing. In known devices clutches usually require additionalcomponents either being interposed between the components to be coupledor decoupled or being used for actuation of the clutch. In contrast tothat, with the present invention two clutches are provided withoutadditional component parts.

Preferably, the button comprises a set of clutch teeth and the displaymember comprises a further set of corresponding clutch teeth, whereinaxial movement of the button relative to the display member engages ordisengages the sets of clutch teeth. The second clutch may be formed bythe above mentioned at least one protrusion of the driver interactingwith splines of the housing.

According to a fifth embodiment of the present invention, this object issolved by a disposable drug delivery device for selecting and dispensinga number of user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, and a button coupledto the display member and to the driver, wherein a first clicker, whichis active during dose setting, is formed by the driver and the housingand a second clicker, which is active during dose dispensing, is formedby the button and the display member. In other words, a clicker forproducing a tactile and/or audible feedback during use of the device isprovided without adding separate components to the device.

According to a sixth embodiment of the present invention, this object issolved by a disposable drug delivery device for selecting and dispensinga number of user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, and a button coupledto the display member and to the driver, wherein the number ofcomponents of the drug delivery device including the cartridge and a capfor shielding the cartridge holder is ten or less. In this respect, thecartridge including its movable rubber type bung, its pierceable rubberseal and e.g. its crimped annular metal band is considered as onecomponent. Known disposable drug delivery devices usually comprisetwelve or more parts, often nearly twenty separate component parts.Taking into account that disposable drug delivery devices aremass-produced, such a significant reduction of component parts resultsin reduced manufacturing costs.

The housing may comprise a transparent or translucent outer body,wherein at least a part of the outer body is coated by an opaque layer.This is especially preferred if the outer body is a one-piece componentwith usually the transparent or translucent cartridge holder. A furtherbenefit of the outer body being transparent or translucent is thatadditional window inserts may be omitted. The opaque, i.e.not-transparent and not-translucent, layer may cover the part of theouter body containing the mechanical dosing components. Especially, thedisplay member, which is typically provided with numbers or the like fordisplaying the set dose, may be at least partly shielded by the opaquelayer such that only the number corresponding to the actually set doseis visible. The opaque layer may be an inner or outer coloured layer, alabel or tag attached to the outer body, a lining attached or otherwisefixed to the outer body or a frosted or scarified surface.

Preferably, the piston rod is a double threaded piston rod having afirst outer thread engaging an internal thread of the housing and asecond outer thread engaging an internal thread of the driver, whereinthe first and second outer threads may overlap each other at leastpartially. This allows to provide a mechanical advantage, i.e. atransmission (gear) ratio, in the device. Typically, the dial extensionof the button, i.e. the distance the button winds out of the housingduring dose setting, will be larger than the distance the piston rod isdisplaced relative to the cartridge holder and thus the cartridge. Thisallows dispensing even small amounts of a medicament with a maximum ofdispensing control by the user.

A further reduction of the number of component parts may be achieved ifthe piston rod comprises a bearing attached to the piston rod by atleast one predefined breakage point. The bearing is axially constrainedbut rotatable with respect to the piston rod after detachment of thebearing by destroying the at least one predefined breakage point duringor after assembly. Thus, only one single component has to be handledduring assembly which in use fulfils the function of two separatecomponents.

According to a preferred embodiment, the driver is a tubular elementhaving a distal portion engaging a nut interposed between the housingand the driver, and a proximal portion which at least partly surrounds atubular portion of the button. Preferably, one of the housing and thedriver comprises at least one spline and the other of the housing andthe driver comprises a threaded portion with the nut interposed betweenthe housing and the driver, wherein the nut comprises at least oneprotrusion engaging the at least one spline and a thread engaging thethreaded portion, and wherein the threaded portion of the housing or thedriver comprises a rotational end stop. If the nut abuts the rotationalend stop, further movement of the nut in the thread is prevented whichthus prevents further rotation of the driver relative to the housingwhich is required during dose setting. Thus, the nut may be used tolimit the settable dose. This is e.g. required to prevent setting a doseexceeding the amount of medicament in the cartridge.

Preferably, one of the driver and the display member comprises acircular groove or a circular track defined by two walls and the otherof the driver and the display member comprises a circular bulge engagingthe groove or track. This allows to constrain the driver and the displaymember in the axial direction but to allow relative rotation.

If the housing comprises an outer body and an inner body, the inner bodymay be rotationally and axially constrained within the outer body suchthat a cylindrical gap exists between the inner body and the outer body.Preferably, the inner body comprises an outer thread engaging an innerthread of the display member and comprises at least one inner splineengaging a protrusion of the driver.

In a standard embodiment, the splines of the inner body are axiallyaligned with the pen device. In an alternative embodiment, it ispossible to reduce dispense force, increase the velocity ratio and toincrease the thread pitch of the display member (i.e. increase offriction coefficient asymptote), by providing the inner body with atleast one inner spline which is helically twisted. In other words, thesplines are not axially aligned, which results in the driver and thebutton traveling helically during dose dispensing. This may requireadding an over-cap for the button as an additional component preventingrelative rotation with respect to a user's hand, typically the thumb,during dose dispensing.

The basic function of the drug delivery device according to the presentinvention may include that a dose is selected by rotating a buttoncomponent, which travels helically during dose setting. A dose may bedelivered by pressing on the same button component, which now movesaxially during dispensing. Preferably, any dose size can be selected, inpredefined increments, between zero and a predefined maximum dose, e.g.80 units. It is a further advantage if the mechanism permits cancellingof a dose without medicament being dispensed, e.g. by rotation of thebutton component in the opposite direction to when selecting a dose.

It is preferred if during dose setting the button is rotated whichentrains the driver and the display member such that the button, thedriver and the display member are moved on a helical path with respectto the housing and the piston rod. Further, during dose dispensing thebutton is axially displaced which entrains the driver and the displaymember such that the button, the driver and the display member areaxially moved with respect to the housing and the piston rod, with thedisplay member and the piston rod rotating with respect to the housing,the button and the driver.

To prevent malfunction or misuse of the device, the dose settingmechanism may be provided with stops preventing dialling of a dose belowzero units or dialling of a dose above a maximum dose. Preferably,rotational hard stops are provided, e.g. between the display member andthe inner body as a zero unit stop and/or as a maximum units stop.

The drug delivery device may comprise a cartridge containing amedicament. The term “medicament”, as used herein, means apharmaceutical formulation containing at least one pharmaceuticallyactive compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(w-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

-   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   des Pro36 Exendin-4(1-39),-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   wherein the group -Lys6-NH2 may be bound to the C-terminus of the    Exendin-4 derivative;-   or an Exendin-4 derivative of the sequence-   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),-   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,-   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]    Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(S1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys6-NH2;-   or a pharmaceutically acceptable salt or solvate of any one of the    afore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H-H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

BRIEF DESCRIPTION OF THE FIGURES

Exemplary embodiments of the invention will now be described withreference to the accompanying drawings, in which:

FIG. 1 shows a perspective view of a drug delivery device in accordancewith the present invention;

FIG. 2 shows in an exploded view the components of the drug deliverydevice of FIG. 1;

FIG. 3a shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a zero unit position;

FIG. 3b shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a 47 units position;

FIG. 3c shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a maximum units position;

FIGS. 4a , b show sectional views of a detail of the drug deliverydevice of FIG. 1;

FIGS. 5a , b show sectional views of a further detail of the drugdelivery device of FIG. 1;

FIG. 6a shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a zero unit position;

FIG. 6b shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a maximum units position;

FIG. 7 shows a cut-away view of a detail of the drug delivery device ofFIG. 1;

FIG. 8 shows a sectional view of a further detail of the drug deliverydevice of FIG. 1;

FIGS. 9a-d show cut-away views of further details of the drug deliverydevice of FIG. 1;

FIG. 10 shows a perspective view of a nut of the drug delivery device ofFIG. 1;

FIG. 11 shows a sectional view of the nut of FIG. 10;

FIGS. 12a, b show cut-away views of further details of the drug deliverydevice of FIG. 1;

FIGS. 13a-c show cut-away views of further details of the drug deliverydevice of FIG. 1;

FIG. 14 shows a perspective view of a nut of the drug delivery device ofFIG. 1;

FIGS. 15a, b show cut-away views of further details of the drug deliverydevice of FIG. 1;

FIG. 16a shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a maximum units position;

FIG. 16b shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a maximum units position with the button pressed;

FIG. 16c shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a zero unit position; and

FIGS. 17a-c show cut-away and sectional views of further details of thedrug delivery device of FIG. 1.

DETAILED DESCRIPTION

FIG. 1 shows a drug delivery device 1 in the form of an injection pen.The device has a distal end (upper end in FIG. 1) and a proximal end(lower end in FIG. 1). The component parts of the drug delivery device 1are shown in FIG. 2 in more detail. The drug delivery device 1 comprisesan outer housing part 10, an inner body 20, a piston rod 30, a driver40, a nut 50, a display member 60, a button 70, a cartridge 80 and a cap90, i.e. in total nine separate component parts. As shown in FIG. 2, aneedle arrangement comprising a needle hub 2 and a needle cover 3 may beprovided as additional components, which can be exchanged as explainedabove.

The outer housing part 10 is a generally tubular element having a distalpart, which forms a cartridge holder 11 for receiving cartridge 80, anda proximal part, which forms an outer body 12. In a preferredembodiment, the outer housing part 10 is transparent, with the outerbody 12 being provided with an opaque layer 13. In FIG. 2, the opaquelayer 13 covers most of the outer body 12 with the exception of atransparent window 14. Apertures 15 may be provided in the cartridgeholder 11. Further, at its distal end the cartridge holder 11 has athread 16 or the like for attaching the needle hub 2.

The inner body 20 is a generally tubular element having differentdiameter regions. As can be seen in FIGS. 16a to 16c , the inner body 20is received in the outer body 12 and permanently fixed therein toprevent any relative movement of the inner body 20 with respect to theouter body 12. An external thread 21 is provided on the outer surface ofthe inner body 20. Further, splines 22 are provided on the inner surfaceof the inner body 20 which are shown in FIGS. 8 and 11. As can be takenfrom FIG. 7, the inner body 20 has near its distal end an inner thread23.

The piston rod 30 is an elongate element having two external threads 31,32 with opposite hand which overlap each other. One of these threads 31engages the inner thread 23 of the inner body 20. A disk-like bearing 33is provided at the distal end of the piston rod 30. As shown in FIG. 2,the bearing 33 may be attached to the piston rod 30 as a one-piececomponent via a predetermined breaking point. This allows that thebearing 33 is separated from the piston rod 30 such that the bearing 33remains seated on the distal end of the piston rod 30 to allow relativerotation between the bearing 33 and the piston rod 30.

The driver 40 is a generally tubular element having different diameterregions. A distal region of the driver 40 has an external thread 41. Aninner surface of the driver 40 has an inner thread 42 (FIGS. 12a and 12b) engaging one of the external threads 32 of the piston rod 30. Thedriver 40 surrounds the piston rod 30 and is at least partly locatedwithin inner body 20. The driver has at least one proximal opening 43which will be explained in more detail below. Further, a resilientfinger 44 (FIGS. 6a and 6b ) is provided on the driver 40 by a U-shapedcut in the skirt of the driver 40. The finger 44 is allowed to flex inthe axial direction and engages button 70. In addition, a flexiblyhinged protrusion 45 (FIGS. 8 and 9 a) is provided on the driver 40 by asimilar cut out in the skirt of the driver 40. The protrusion 45 isallowed to flex radially inwardly and is provided with lateral flaps 46.Protrusion 45 engages splines 22 of the inner body 20.

The nut 50 is provided between the inner body 20 and the driver 40.External ribs 51 of the nut 50 engage splines 22 of the nut 50. Aninternal thread 52 of the nut engages the external thread 41 of thedriver 40. As an alternative, splines and ribs could be provided on theinterface between the nut 50 and the driver 40 and threads could beprovided on the interface between the nut 50 and the inner body 20. As afurther alternative, the nut 50 may be designed as e.g. a half nut.Further, in the embodiment of FIG. 10, four rotational hard stops 53 areprovided on nut 50 for interaction with corresponding stops 47 on thedriver 40 at the proximal end of thread 41.

The display member 60 is a generally tubular element with an internalthread 61 engaging the external thread 21 of the inner body 20. Thus,the display member 60 is interposed between the inner body 20 and theouter body 12. A series of numbers is provided, e.g. printed, on theouter surface of the display member 60. The numbers are arranged on ahelical line such that only one number or only a few numbers are visiblein through window 14 of the outer body 12. As will be explained in moredetail below, the display member 60 is attached to the driver 40preventing relative axial movement but allowing relative rotation.

FIGS. 4a and 4b show in more detail a zero unit rotational hard stopformed by a stop wall 62 in thread 61 of the display member 60 and acorresponding stop face 24 on the inner body 20. FIGS. 5a and 5b show inmore detail a maximum dose (e.g. a 80 units) rotational hard stop formedby a finger 63 at the distal end of the display member 60 and aprotrusion 25 in thread 21 of the inner body 20. Thus, a user isprevented from dialing below zero units and above e.g. 80 units.

The button 70 has a proximal end with an, e.g. serrated, flange or outerskirt 71 allowing a user to easily grip and dial button 70. Asleeve-like part 72 of the button 70 with a reduced diameter extends inthe distal direction and is inserted into the driver 40 such that alimited relative axial movement is allowed but relative rotation isprevented. This is achieved by a rib 73 on the sleeve-like part 72 whichis guided in a proximal opening 43 of the driver 40. A recess 73 whichgenerally has the outline of the protrusion 45 and its lateral flaps 46is provided in the sleeve-like part 72 of button 70.

A clutch is provided between the display member 60 and the button 70 bycorresponding teeth 64 and 74 (FIGS. 13a and 13b ). If teeth 74 of thebutton 70 engage teeth 64 of the display member 60, these components arerotationally locked. The resilient finger 44 of the driver 40 biases thebutton 70 in the proximal direction of the device 1, i.e. in a directionengaging the clutch teeth. The clutch can be released allowing relativerotation by shifting the button 70 axially with respect to the displaymember 60 against the bias of finger 44.

Further, a dispense clicker is provided by flexible arms 65 on thedisplay member 60 and a toothed profile 75 on the inner side of flange71 of button 70. This clicker is shown in FIGS. 17a to 17 c.

The cartridge 80 includes a pre-filled, necked-down cartridge reservoir81, which may be typically made of glass. A rubber type bung 82 orstopper is located at the proximal end of the cartridge reservoir 81,and a pierceable rubber seal (not shown) is located at the other,distal, end. A crimped annular metal band 83 is used to hold the rubberseal in place. The cartridge 80 is provided within the cartridge holder11 with bearing 33 of piston rod 30 abutting bund 82.

FIG. 1 shows the cap 90 attached to the distal end of the device 1, thuscovering the cartridge holder 11. The cap 90 may be releasable snappedonto the outer housing 10 and can be taken off for use of the device 1.

In the following, the function of the disposable drug delivery device 1and its components will be explained in more detail.

To use the device, a user has to select a dose. In the start (at rest)condition as shown in FIGS. 3a and 6a the display member 60 indicatesthe number of doses dialed to the user. The number of dialed units canbe viewed through the dose window 14 in the outer body 12. Due to thethreaded engagement between the display member 60 and the inner body 20rotation of the button 70 in a clockwise fashion causes the displaymember 60 to wind out of the device and incrementally count the numberof units to be delivered. FIG. 3b shows an intermediate stage of dialing(47 of 80 units).

During dose setting button 70, driver 40 and display member 60 arerotationally locked together via clutch teeth 64, 74. Further, button70, driver 40 and display member 60 are axially coupled. Thus, thesethree components wind out of the outer housing 10 during dose setting.

Clockwise rotation of the button 70 causes the driver 40 to rotate andin doing so it advances along the piston rod 30 which remains fixedthroughout dialing.

The protrusion 45 and splines 22 form a clicker arrangement thatprovides tactile and audible feedback to the user when dialing doses.This clicker arrangement has the further functions of defining discretepositions for the display member 60 when dialing and of providing amethod of locking the rotation of the driver 40 and hence button 70 whendosing. During dialing (dose setting) the button 70 is in an axialposition relative to the driver 40 such that the pocket or recess 73 islocated radially inwards of the protrusion. Thus, the protrusion 45 isallowed to flex radially inwards to overcome splines 22 therebyproviding a tactile and audible feedback to the user. FIG. 8 shows theflexible protrusion arm 45 located between splines 22 which are e.g. 15°apart.

At the maximum settable dose of 80 units, the stop features 63, 25 shownin FIGS. 5a and 5b engage to prevent further dialing. This position ofthe device is shown in FIGS. 3c and 6 b.

The last dose nut 50 provides the function of counting the number ofdispensed units. The nut 50 locks the device 1 at the end of life and assuch no more drug can be dialed or dispensed by the user. The last dosenut 50 and the driver 40 are connected via a threaded interface 41, 52as explained above. Further, the last dose nut 50 is assembled intosplines 22 as shown in FIG. 11 such that the nut 50 and the inner body20 are rotationally locked together (at all times). Rotation of thedriver 40 during dialing causes the nut 50 to advance along the driver40 thread 41. The nut 50 is free to slide axially within the inner body20 at all times which allows advancement of the nut. The change in pitchshown in FIGS. 12a and 12b towards the final doses axially acceleratesthe advancement of the nut 50 towards the end of life lockout condition.At the end of life condition, the stop features 53 of the last dose nut50 contact the corresponding features 47 on the driver 40. The splinedcontact with inner body 20 reacts any torque transmitted by these stopfeatures 47.

With the desired dose dialed, the device 1 is ready for dose dispensing.This basically requires pushing button 70 which will result in adisengagement of the clutch teeth 64, 74. As mentioned above, whendialing a dose the button 70 is ‘biased out’ and the clutch features 64,74 which rotationally lock the driver 40, button 70 and display member60 together are engaged as shown in FIG. 15a . Upon pressing the button70 the clutch features 64, 74 disengage as shown in FIG. 15b andrelative rotation between the display member 60 and the button 70 ispossible. In all conditions the driver 40 and the button 70 arerotationally locked together by engagement rib 73 and opening 43. Thus,with the clutch 64, 74 disengaged (button 70 pushed in) button 70 anddriver 40 are rotationally locked together with the button 70, thedriver 40 and the display member 60 still being axially coupled.

At the same time the relative axial movement of the button 70 withrespect to the driver 40 results in the pocket or recess 73 beingshifted relative to the protrusion 45. Thus, the protrusion 45 isprevented from flexing inwards because flaps 46 rest on a non-recessedarea of button 70. A comparison of FIGS. 9c and 9d shows this activationof the lockout feature preventing the flexible protrusion arm 45 fromovercoming splines 22 if the button 70 is pressed. In this condition,the driver 40 and the button 70 are rotationally constrained to theinner body 20 thus preventing any rotation relative to the outer housing10 if the splines 22 are axially aligned with the device as shown inFIG. 13c . The above mentioned alternative embodiment with twistedsplines 22 is shown in FIG. 14.

With the desired dose dialed the button 70 can be depressed and thepiston rod 30 driven forward to dispense drug from the cartridge. Theinteraction of mating threads between the piston rod 30, driver 40 andinner body 20 delivers a mechanical advantage of 2:1. The sequence ofdispensing is depicted in FIGS. 16a to 16c with FIG. 16a showing thedevice 1 with 80 units dialed prior to pushing button 70, FIG. 16b showsthe device 1 with 80 units dialed and button 70 pushed and FIG. 16cshows the device 1 with 80 units dispensed.

During dose dispensing a dispense clicker is active which involvesbutton 70 and display member 60. The dispense clicker provides primarilyaudible feedback to the user that drug is being dispensed. Theinteraction between the flexible arms 65 on the display member 60 andthe toothed profile 75 on the button flange 71 provide this dispenseclick. Relative rotation is only allowed in one direction. This occurswhen the components are decoupled during dispense and a click isproduced for every unit.

1-17. (canceled)
 18. A drug delivery device for selecting and dispensinga number of user variable doses of a medicament, the drug deliverydevice comprising: a housing; a cartridge holder for retaining acartridge containing the medicament; a piston rod displaceable relativeto the cartridge holder; and a driver coupled to the piston rod, whereinthe housing comprises a transparent or translucent outer body, whereinat least a part of the outer body is coated by an opaque layer.
 19. Thedrug delivery device of claim 18, wherein the opaque layer is an inneror outer coloured layer.
 20. The drug delivery device of claim 18,wherein the opaque layer is a label or tag attached to the outer body.21. The drug delivery device of claim 18, wherein the opaque layer is alining attached or otherwise fixed to the outer body.
 22. The drugdelivery device of claim 18, wherein the opaque layer is a frosted orscarified surface.
 23. The drug delivery device of claim 18, wherein theouter body is a one-piece component.
 24. The drug delivery device ofclaim 18, wherein the opaque layer covers a portion of the outer bodycontaining mechanical dosing components.
 25. The drug delivery device ofclaim 18, wherein a total quantity of components of the drug deliverydevice including the cartridge and a cap for shielding the cartridgeholder is ten or fewer.
 26. The drug delivery device of claim 18,wherein the drug delivery device is a disposable drug delivery device.27. The drug delivery device of claim 18, comprising a display memberfor indicating a set dose and being coupled to the housing and to thedriver.
 28. The drug delivery device of claim 27, comprising a buttoncoupled to the display member and to the driver.
 29. The drug deliverydevice of claim 18, wherein the outer body of the housing is a one-piececomponent with the cartridge holder.